title: HE3286, an orally bioavailable synthetic analogue of an active DHEA metabolite suppresses spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse.
abstract: 5-Androstene-3β,7β,17β-triol (AET) is a naturally occurring anti-inflammatory adrenal steroid that limits acute and chronic inflammation. HE3286 (17α-ethynyl-5-androstene-3β,7β,17β-triol) is a synthetic derivative of AET with improved pharmaceutical properties and efficacy in some animal models of autoimmunity. Here, daily oral doses of HE3286 led to a suppression of spontaneous autoimmune diabetes in the non-obese diabetic mouse model of type 1 diabetes mellitus when administered either shortly before or after the first incidence of disease onset. Efficacy was associated with reduced insulitis and a suppression of the pathogenic T helper cell type 1 and type 17 phenotypes in peripheral lymphoid organs. These results demonstrate that daily oral treatment with HE3286 administrated relatively late in the destructive autoimmune process led to a suppression of type 1 diabetes mellitus onset and of the pathological inflammatory status, supporting its clinical evaluation in type 1 diabetes mellitus subjects.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Kosiewicz
authors.forename: Dominick L
authors.initials: DL
authors.lastname: Auci
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Caponnetto
authors.forename: Colleen F
authors.initials: CF
authors.lastname: Tucker
authors.forename: Nabeel
authors.initials: N
authors.lastname: Azeem
authors.forename: Steven K
authors.initials: SK
authors.lastname: White
authors.forename: James M
authors.initials: JM
authors.lastname: Frincke
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Reading
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015704:CD4 Antigens / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D007515:Islets of Langerhans / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C524733:17-ethynyl-5-androstene-3, 7, 17-triol; D015704:CD4 Antigens; D003687:Dehydroepiandrosterone